The healing of wounds is a complex process which is often further complicated by the presence of non-viable, necrotic tissue in the wound area. Debridement is the process of removing the non-viable tissue from a wound to prevent infection and facilitate healing.
Considerable efforts have been made to discover materials capable of distinguishing between viable and non-viable tissue. The discovery of materials which would digest devitalized tissue while not attacking viable tissue would make it possible to remove the devitalized tissue without surgery. It would be a beneficial therapeutic agent in virtually all disease processes where topically devitalized tissue needs to be removed from the viable organism such as burns, decubitus ulcers, pressure necroses, incisional, traumatic and pyogenic wounds, and ulcers secondary to peripheral vascular disease.
One area that has attracted considerable attention is the use of proteolytic enzymes and other chemicals to effect the early debridement of eschar tissue, resulting from burns. Such devitalized tissue is an excellent culture medium and the principal source of the septicemia which is the proximate cause of death in the majority of severely burned patients.
In burns, the devitalized tissue is referred to as eschar. Burn eschar is a complex mixture of dried blood, purulent exudates, and denatured proteins normally found in the epidermal and dermal skin layers. The denatured proteins found in eschar are primarily collagen, elastin, fibrin, hemoglobin, and other coagulated proteins.
For a proteolytic enzyme to be most useful as a debriding agent, particularly for burns, it is desirable for the protease to distinguish between viable and non-viable tissue; readily and thoroughly hydrolyze a wide variety of denatured proteins found in eschar; function at physiological pH and temperature; be compatible with adjunct therapies (e.g., cleansing agents, topical antibiotics); not interfere with normal wound healing or complicate skin grafting; and remain stable in various formulations and at a wide range of temperatures. A number of proteolytic enzyme preparations have been used as debriding agents with varying degrees of success.
Travase.RTM. ointment, which is a preparation containing proteolytic enzymes obtained from sterile filtrates of Bacillus subtilis, is another known enzymatic debriding agent (Garrett, Clinical Medicine (1969) 76:11-15) and U.S. Pat. No. 3,409,719. Crikelair (U.S. Pat. No. 4,276,281) describes the use of elastase, a serine protease derived from pancreas, as an enzymatic debridement agent. Klein et al. (U.S. Pat. No. 4,329,430) describe a proteolytic enzyme mixture derived from bromelin which is useful for the digestion, dissection and separation of non-viable, devitalized tissue. Schmitt (U.S. Pat. No. 3,983,209) teaches treating burns in animals by applying enzymes to a burn surface for debridement of eschar and necrotic tissue. The enzymes disclosed included papain, trypsin, lysozyme, streptokinase, fibrinolysin, pinguinain, Travase and bromelain in a specified hydrophobic polymer. Bioerosion over prolonged periods of time slowly released the proteolytic enzymes.
Merkel (U.S. Pat. No. 3,677,900) discloses that collagenases, especially those produced by a species of Vibrio, are useful as debriding agents. However, Merkel's collagenase is an enzyme capable of digesting native, undenatured collagen under physiological conditions of pH and temperature and is not inhibited by serum. The Merkel collagenase therefore is not likely to distinguish between viable and non-viable tissue. Collagenases also have a very narrow substrate specificity. Further, collagenase has been reported to cause significant damage to viable dermal tissue, causing reduced granulation tissue development and wound maturation (Hamit et al., Ann. Surg. (1960) 151:589).
While other proteolytic debriding agents are known, many of these agents have been shown to be ineffective and cause local or systemic toxicity. None of the previous proteolytic debriding agents have the superior characteristics of the present invention, including the ability to act as a wound healing agent.